Does obesity-associated dyslipidemia predispose myeloid cells to develop a pro-tumorigenic phenotype? 4506

Description Background Obesity is associated with increased severity of different malignancies. Because inflammation predisposes to the development of cancer and promotes all stages of tumorigenesis, we hypothesize that myeloid cell precursors, functionally shaped by dyslipidemia, facilitate tumor development. This study aimed to assess the contribution of obesity-related excess lipids in priming myeloid cells to become cells with pro-tumorigenic properties Methods Immature myeloid cells (IMCs) from diet-induced obesity (DIO) and lean mice were obtained from bone marrow and cultured in vitro with pro-inflammatory cytokines and myeloid growth factors. IMCs were exposed to visceral adipose tissue-conditioned media (VAT-CM), LDL-cholesterol (LDLc), and PCa tumor-derived explant (PCa-TES). Molecular (protein, RNAseq, ATACseq) and functional assessments were performed on IMCs. Coculture of IMCs with 3D PCa and breast cancer (BCa) spheroid were also performed Results VAT-CM, LDLc, and TES increased the expression of immunosuppressive markers in IMCs. However, while the intensity of response to obese-derived signals (VAT-CM and LDLc) was higher by lean IMCs, DIO IMCs exhibited a more intense response towards TES. Integration of RNAseq-ATACseq suggests that lipid-exposed IMCs have an epigenetically regulated activation program. Lipid-preconditioned IMCs also facilitated PCa and BCa spheroid growth Conclusion LDLc and dysfunctional fat-derived factors prime IMCs to become pro-tumorigenic cells Funding Sources U54-GM104940 (Pilot grant); LSU LCMC Health Cancer Center.